Boosting bacillus Calmette-Guérin (BCG)-primed mice with a recombinant adenovirus expressing Mycobacterium tuberculosis Ag 85A by different administration routes has very different effects on ...protection against aerosol challenge with M. tuberculosis. Mice boosted intradermally make very strong splenic CD4 and CD8 Th1 cytokine responses to Ag 85A, but show no change in lung mycobacterial burden over BCG primed animals. In contrast, intranasally boosted mice show greatly reduced mycobacterial burden and make a much weaker splenic response but a very strong lung CD4 and CD8 response to Ag 85A and an increased response to purified protein derivative. This effect is associated with the presence in the lung of multifunctional T cells, with high median fluorescence intensity and integrated median fluorescence intensity for IFN-gamma, IL-2, and TNF. In contrast, mice immunized with BCG alone have few Ag-specific cells in the lung and a low proportion of multifunctional cells, although individual cells have high median fluorescence intensity. Successful immunization regimes appear to induce Ag-specific cells with abundant intracellular cytokine staining.
Factors and processes determining heterogeneous ('patchy') population distributions in natural environments have long been a major focus in ecology. Existing theoretical approaches proved to be ...successful in explaining vegetation patterns. In the case of animal populations, existing theories are at most conceptual: they may suggest a qualitative explanation but largely fail to explain patchiness quantitatively. We aim to bridge this knowledge gap. We present a new mechanism of self-organized formation of a patchy spatial population distribution. A factor that was under-appreciated by pattern formation theories is animal sociability, which may result in density dependent movement behaviour. Our approach was inspired by a recent project on movement and distribution of slugs in arable fields. The project discovered a strongly heterogeneous slug distribution and a specific density dependent individual movement. In this paper, we bring these two findings together. We develop a model of density dependent animal movement to account for the switch in the movement behaviour when the local population density exceeds a certain threshold. The model is fully parameterized using the field data. We then show that the model produces spatial patterns with properties closely resembling those observed in the field, in particular to exhibit similar values of the aggregation index.
Adjuvants enhance or modify an immune response that is made to an antigen. An antagonist of the chemokine CCR4 receptor can display adjuvant-like properties by diminishing the ability of CD4+CD25+ ...regulatory T cells (Tregs) to down-regulate immune responses.
Here, we have used protein modelling to create a plausible chemokine receptor model with the aim of using virtual screening to identify potential small molecule chemokine antagonists. A combination of homology modelling and molecular docking was used to create a model of the CCR4 receptor in order to investigate potential lead compounds that display antagonistic properties. Three-dimensional structure-based virtual screening of the CCR4 receptor identified 116 small molecules that were calculated to have a high affinity for the receptor; these were tested experimentally for CCR4 antagonism. Fifteen of these small molecules were shown to inhibit specifically CCR4-mediated cell migration, including that of CCR4(+) Tregs.
Our CCR4 antagonists act as adjuvants augmenting human T cell proliferation in an in vitro immune response model and compound SP50 increases T cell and antibody responses in vivo when combined with vaccine antigens of Mycobacterium tuberculosis and Plasmodium yoelii in mice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT Background The beneficial off‐target effects of Bacille Calmette–Guérin (BCG) vaccination potentially include protection against allergy. Objective In the MIS BAIR trial, we aimed to ...determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants. Methods In this randomised controlled trial, 1272 neonates were allocated to BCG‐Denmark vaccine (0.05 mL intradermal dose) or no BCG at birth. Randomisation was stratified by recruitment site, mode of delivery and plurality of birth. The primary outcome was the incidence of atopic sensitisation determined by skin prick test at 1 year of age. Food allergy was determined by 3‐monthly online questionnaires and oral food challenges. Data were analysed by intention‐to‐treat using binary regression. Clinicaltrials.gov ( NCT01906853 ). Results Atopic sensitisation during the first year of life was 22.9% among infants in the BCG group and 18.9% in the control group (adjusted risk difference (aRD) 3.8% (95% CI −1.5 to 9.1) after multiple imputation). Clinical food allergy was similar between infants in the BCG and control groups (9.8% vs. 9.6%; aRD 0.2, 95% CI −3.4 to 3.8). An interaction was observed between the primary outcome and maternal history of BCG vaccination. No interaction was observed for the additional prespecified potential effect modifiers tested (sex, delivery mode, family history of any allergy, season of birth, hepatitis B vaccination at randomisation, BCG scar and age at BCG administration). Conclusions and Clinical Relevance Neonatal BCG‐Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life.
Identification of correlates of protection for infectious diseases including malaria is a major challenge and has become one of the main obstacles in developing effective vaccines. We investigated ...protection against liver-stage malaria conferred by vaccination with adenoviral (Ad) and modified vaccinia Ankara (MVA) vectors expressing pre-erythrocytic malaria Ags. By classifying CD8(+) T cells into effector, effector memory (T(EM)), and central memory subsets using CD62L and CD127 markers, we found striking differences in T cell memory generation. Although MVA induced accelerated central memory T cell generation, which could be efficiently boosted by subsequent Ad administration, it failed to protect against malaria. In contrast, Ad vectors, which permit persistent Ag delivery, elicit a prolonged effector T cell and T(EM) response that requires long intervals for an efficient boost. A preferential T(EM) phenotype was maintained in liver, blood, and spleen after Ad/MVA prime-boost regimens, and animals were protected against malaria sporozoite challenge. Blood CD8(+) T(EM) cells correlated with protection against malaria liver-stage infection, assessed by estimation of number of parasites emerging from the liver into the blood. The protective ability of Ag-specific T(EM) cells was confirmed by transfer experiments into naive recipient mice. Thus, we identify persistent CD8 T(EM) populations as essential for vaccine-induced pre-erythrocytic protection against malaria, a finding that has important implications for vaccine design.
Viral vectored vaccines have been shown to induce both T cell and antibody responses in animals and humans. However, the induction of even higher level T cell responses may be crucial in achieving ...vaccine efficacy against difficult disease targets, especially in humans. Here we investigate the oligomerization domain of the α-chain of C4b-binding protein (C4 bp) as a candidate T cell "molecular adjuvant" when fused to malaria antigens expressed by human adenovirus serotype 5 (AdHu5) vectored vaccines in BALB/c mice. We demonstrate that i) C-terminal fusion of an oligomerization domain can enhance the quantity of antigen-specific CD4(+) and CD8(+) T cell responses induced in mice after only a single immunization of recombinant AdHu5, and that the T cells maintain similar functional cytokine profiles; ii) an adjuvant effect is observed for AdHu5 vectors expressing either the 42 kDa C-terminal domain of Plasmodium yoelii merozoite surface protein 1 (PyMSP1(42)) or the 83 kDa ectodomain of P. falciparum strain 3D7 apical membrane antigen 1 (PfAMA1), but not a candidate 128kDa P. falciparum MSP1 biallelic fusion antigen; iii) following two homologous immunizations of AdHu5 vaccines, antigen-specific T cell responses are further enhanced, however, in both BALB/c mice and New Zealand White rabbits no enhancement of functional antibody responses is observed; and iv) that the T cell adjuvant activity of C4 bp is not dependent on a functional Fc-receptor γ-chain in the host, but is associated with the oligomerization of small (<80 kDa) antigens expressed by recombinant AdHu5. The oligomerization domain of C4 bp can thus adjuvant T cell responses induced by AdHu5 vectors against selected antigens and its clinical utility as well as mechanism of action warrant further investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often ...induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants. We have therefore taken an approach to adjuvant discovery that uses in silico modeling and structure-based drug-design. As proof-of-principle we chose to target the interaction of the chemokines CCL22 and CCL17 with their receptor CCR4. CCR4 was posited as an adjuvant target based on its expression on CD4⁺CD25⁺ regulatory T cells (Tregs), which negatively regulate immune responses induced by dendritic cells (DC), whereas CCL17 and CCL22 are chemotactic agents produced by DC, which are crucial in promoting contact between DC and CCR4⁺ T cells. Molecules identified by virtual screening and molecular docking as CCR4 antagonists were able to block CCL22- and CCL17-mediated recruitment of human Tregs and Th2 cells. Furthermore, CCR4 antagonists enhanced DC-mediated human CD4⁺ T cell proliferation in an in vitro immune response model and amplified cellular and humoral immune responses in vivo in experimental models when injected in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis (MVA85A) or recombinant hepatitis B virus surface antigen (rHBsAg) vaccines. The significant adjuvant activity observed provides good evidence supporting our hypothesis that CCR4 is a viable target for rational adjuvant design.
In international law the right of every people to self-determination is well established. Yet in terms of substance and process this right incident to 'peoplehood', on its face the paradigmatically ...collectively held right, is inadequately articulated. This paper interrogates the normative status of self-determination in the context of colonial domination, after the Advisory Opinion on the Legal Consequences of the Separation of the Chagos Archipelago from Mauritius in 1965 ('Chagos Advisory Opinion') issued by the International Court of Justice ('ICJ') in 2019. Self-determination is investigated both as a putative norm of customary international law ('CIL') and a putative norm jus cogens. The CIL status of self-determination in the post-colonial setting is well established by the ICJ and a higher, peremptory status is strongly implied. In either case territorial integrity is of the essence of the rights conveyed by the norm. Here it is argued that while the formal status of a norm of self-determination is thus to some extent clarified by the Chagos Advisory Opinion, the substance of such a norm remains insufficiently articulated. If anything, the emphasis on territorial integrity compromises the status of peoplehood and conveys that the incidents of statehood take precedence over the collective rights of distinct populations.
Immunopathology of placental malaria is most significant in women in their first pregnancy especially in endemic areas, due to a lack of protective immunity to Plasmodium falciparum, which is ...acquired in successive pregnancies. In some studies (but not all), grand multigravidae (defined as 5 or more pregnancies, G5-7) are more susceptible to poor birth outcomes associated with malaria compared to earlier gravidities. By comparing peripheral cellular responses in primigravidae (G1), women in their second to fourth pregnancy (G2-4) and grand multigravidae we sought to identify key components of the dysregulated immune response. PBMC were exposed to CS2-infected erythrocytes (IE) opsonised with autologous plasma or unopsonised IE, and cytokine and chemokine secretion was measured. Higher levels of opsonising antibody were present in plasma derived from multigravid compared to primigravid women. Significant differences in the levels of cytokines and chemokines secreted in response to IE were observed. Less IL-10, IL-1β, IL-6 and TNF but more CXCL8, CCL8, IFNγ and CXCL10 were detected in G5-7 compared to G2-4 women. Our study provides fresh insight into the modulation of peripheral blood cell function and effects on the balance between host protection and immunopathology during placental malaria infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Malaria‐specific antibody‐dependent respiratory burst activity from neutrophils is acquired in mice following infection; however, vaccination with a leading vaccine antigen fails to induce this ...activity.
New tools are required to expedite the development of an effective vaccine against the blood‐stage infection with the human malaria parasite Plasmodium falciparum. This work describes the assessment of the ADRB assay in a mouse model, characterizing the functional interaction between antimalarial serum antibodies and FcRs upon neutrophils. We describe a reproducible, antigen‐specific assay, dependent on functional FcR signaling, and show that ADRB activity is induced equally by IgG1 and IgG2a isotypes and is modulated by blocking FcR function. However, following immunization of mice with the blood‐stage vaccine candidate antigen MSP142, no measurable ADRB activity was induced against PEMS and neither was vaccine efficacy modulated against Plasmodium yoelii blood‐stage challenge in γ−/− mice compared with WT mice. In contrast, following a primary, nonlethal P. yoelii parasite challenge, serum from vaccinated mice and nonimmunized controls showed anti‐PEMS ADRB activity. Upon secondary challenge, nonimmunized γ−/− mice showed a reduced ability to control blood‐stage parasitemia compared with immunized γ−/− mice; however, WT mice, depleted of their neutrophils, did not lose their ability to control infection. Thus, whereas neutrophil‐induced ADRB against PEMS does not appear to play a role in protection against P. yoelii rodent malaria, induction of ADRB activity after challenge suggests that antigen targets of anti‐PEMS ADRB activity remain to be established, as well as further supporting the observation that ADRB activity to P. falciparum arises following repeated natural exposure.
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